INTRODUCTION TO ANTIBIOTICS, PENICILLIN, CEPHALOSPORIN, AMINOGLYCOSIDES, CHLORAMPHENICOL, TETRACYCLIN.

1. ANTIBIOTICS
Dr. BASAVARAJAIAH S. M.
Assistant Professor and Coordinator
P.G. Department of Chemistry
Vijaya College
Bangalore-560 004

2. CONTENTS
1.INTRODUCTION TO ANTIBIOTICS
2.PENICILLIN
3.CEPHALOSPORIN
4.AMINOGLYCOSIDES
5.CHLORAMPHENICOL
6.TETRACYCLIN

3. HISTORY OF ANTIBIOTICS
19th Century: – Louis Pasteur & Robert Koch: Bacteria as
causative agents & recognized need to control them.
Plant extracts – Quinine (against malaria)
Toxic metals – Mercury (against syphilis) – Arsenic (Atoxyl,
against Trypanosoma)
Dyes – Trypan Blue (Ehrlich) – Prontosil (azo-dye, Domagk, 1936)
Paul Ehrlich;
Started science of chemotherapy
Systematic chemical modifications
1.INTRODUCTION TO ANTIBIOTICS

4. Penicillin- the first antibiotic – 1928
Alexander Fleming observed the killing of
staphylococci by a fungus (Penicillium notatum)
observed by others - never exploited
Florey & Chain purified it by freeze drying (1940)
Nobel prize 1945
First used in a patient: 1942 •
World War II: penicillin saved 12-15% of lives

5. Selman Waksman - Streptomycin (1943)
Active against all Gram-negatives
First antibiotic active against Mycobacterium
tuberculosis
Most severe infections were caused by
Gram-negatives and Mycobacterium
tuberculosis
Extracted from Streptomyces
20 other antibiotics, incl. neomycin,
actinomycin

6. Definition: Substance produced by a microorganism
[synthetic or semisynthetic] that is capable, in low concentrations,
of inhibiting the growth of or killing other microoganisms.
Ex; Penicillin, Cephalosporin, Tetracycline etc
ANTIBIOTIC

7. MODE OF ACTIONS OF ANTIBIOTICS

9. CLASSES OF ANTIBIOTICS
1. β-Lactam antibiotics examples: Penicillins (e.g.
amoxicillin), cephalosporins, carbapenems,
monobactams, etc.
2. Tetracyclines example: Tetracycline
3. Macrolide antibiotics example: Erythromycin
4. Aminoglycosides examples: Gentamicin, Tobramycin,
Amikacin
5. Quinolones example: Ciprofloxacin (a fluoroquinolone)
6. Cyclic peptides examples: Vancomycin, Streptogramins,
Polymyxins

10. 7. Lincosamides example: Clindamycin
8. Oxazolidinoes example: Linezolid (Zyvox)
9. Sulfa antibiotics example: Sulfisoxazole

12. 2. PENICILLIN
In 1929, Alexander Fleming isolated penicillin from a strain of
Penicillium notatum. By 1941, benzylpenicillin could be produced
in sufficient quantity to treat several infected patients.
Clinical trials with the agent, conducted by Florey and
colleagues, were successful and during World War II,
benzylpenicillin was used to treat patients with streptococcal,
gonococcal, and treponemal infections.
Shortages of the agent continued until the late 1940s when the
production of large amounts of the drug became possible by a
deep-fermentation procedure.

13. Since then, many synthetic penicillins have been developed, but
resistance to the agents has increased.
Despite the emergence of resistance to penicillins and the
development of other classes of anti-infective agents, the
penicillins remain one of the most important anti-infective classes
of drugs well into the nineties.
Penicillin G is still the drug of choice for many types of
infections, including syphilis and certain types of endocarditis

14.  The basic chemical structure of all penicillins consists of a β-
lactam ring, a thiazolidine ring, and a side chain (6-
aminopenicillanic acid).
 The antibacterial activity of the penicillins lies within the β-
lactam ring.
 Any alteration in this ring structure forms penicilloic acid and
the antibacterial activity of the compound is lost.
 The side chain varies with each penicillin compound and
generally determines the spectrum of activity, as well as the
pharmacokinetic properties of the compound.

15.  There are several natural penicillins (penicillin dihydro F, X, and K),
of which benzylpenicillin (penicillin G) is the most active and is the only
natural penicillin used clinically.

17. Synthesis of penicillin G (Biosynthesis):

18. Synthesis of penicillin G (Chemical synthesis):

19. Some important reactions of penicillin:

22. By binding to specific penicillin-binding proteins (PBPs) located
inside the bacterial cell wall.
Penicillin G inhibits the third and last stage of bacterial cell wall
synthesis.
Cell lysis is then mediated by bacterial cell wall autolytic
enzymes such as autolysins; penicillin G may interfere with an
autolysin inhibitor.
MECHANISM OF ACTION

23. The cephalosporin's are a class of β-lactam antibiotics originally
derived from the fungus Acremonium, which was previously
known as "Cephalosporium".
Together with cephamycins, they constitute a subgroup of β-
lactam antibiotics called cephems.
The aerobic mold which yielded cephalosporin C was found in
the sea near a sewage outfall in Su Siccu, by Cagliari harbour
in Sardinia, by the Italian pharmacologist Giuseppe Brotzu in
July 1945.
3. CEPHALOSPORIN

26. CEPHALOSPORIN-C
Cephalosporin C is an antibiotic of the cephalosporin class. It
was isolated from a fungus of the genus Acremonium and first
characterized in 1961.
Although not a very active antibiotic itself, synthetic analogs of
cephalosporin C, such as cefalotin, became some of the first
marketed cephalosporin antibiotic drugs.
Cephalosporin C strongly absorbs ultraviolet light, is stable to
acid, is non-toxic and has in vivo activity in mice.

27. Cephalosporin C, which has a similar structure to penicillin N,
was never commercialized.
Cephalosporin C was a lead compound for the discovery and
production of many other cephalosporins.
Cephalosporins are drugs used for some people who are
allergic to penicillin.
Cephalosporins are used to treat bacterial infections such as
respiratory tract infections, skin infections and urinary tract
infections.
When a cephalosporin or any other antibiotic is given as a
treatment, the medication should be taken for the fully prescribed
time even if symptoms disappear.

28. BIOSYNTHESIS OF CEPHALOSPORIN-C

29. CEPHALOSPORINS CHEMICAL SYNTHESIS

33. Complete:

34. Conversion of penicillin to cephalosporin

35. Cephalosporins are bactericidal and have the same mode of
action as other β-lactam antibiotics (such as penicillins), but are
less susceptible to β-lactamases.
Cephalosporins disrupt the synthesis of the peptidoglycan
layer forming the bacterial cell wall.
MODE OF ACTION

36. 4. AMINOGLYCOSIDES
Aminoglycoside is a medicinal and bacteriologic category of
traditional Gram-negative antibacterial medications that inhibit
protein synthesis and contain as a portion of the molecule an
amino-modified glycoside (sugar).
The term can also refer more generally to any organic molecule
that contains amino sugar substructures.
 Aminoglycoside antibiotics display bactericidal activity against
Gram-negative aerobes and some anaerobic bacilli where
resistance has not yet arisen but generally not against Gram-
positive and anaerobic Gram-negative bacteria.

37. Streptomycin is the first-in-class aminoglycoside antibiotic. It
is derived from Streptomyces griseus and is the earliest
modern agent used against tuberculosis.
Streptomycin lacks the common 2-deoxystreptamine moiety
present in most other members of this class.
Other examples of aminoglycosides include the
deoxystreptamine-containing agents kanamycin,
tobramycin, gentamicin, and neomycin.

39. STREPTOMYCIN
Streptomycin is an antibiotic medication used to treat a number
of bacterial infections, including tuberculosis, Mycobacterium
avium complex, endocarditis, brucellosis, Burkholderia infection, p
lague, tularemia, and rat bite fever.
Albert Schatz first isolated streptomycin in 1943
from Streptomyces griseus.
It is on the World Health Organization's List of Essential
Medicines.
The World Health Organization classifies it as critically important
for human medicine.

40. Streptomycin structure has been shown to be composed of the
three unit’s Streptose (I), N-methyl-L-glucosamine (II), and
Streptadine (III).

41. Medical uses of Streptomycin:
Infective endocarditis
Tuberculosis
Plague
In veterinary medicine
Tularemia
Streptomycin also is used as a pesticide, to combat the growth
of bacteria beyond human applications.
Streptomycin, in combination with penicillin, is used in a
standard antibiotic cocktail to prevent bacterial infection in cell
culture.

42. STREPTOMYCIN BIOSYNTHESIS

43. Sketch the synthesis of streptomycin from dihydrostreptomycin.
Ans:
Dihydrostreptomycin
Streptomycin

44. MECHANISM OF ACTION OF STREPTOMYCIN
Streptomycin is a protein synthesis inhibitor.
It binds to the small 16S rRNA of the 30S subunit of the
bacterial ribosome irreversibly, interfering with the binding
of formyl-methionyl-tRNA to the 30S subunit.
This leads to codon misreading, eventual inhibition of protein
synthesis and ultimately death of microbial cells through
mechanisms that are still not understood.
Speculation on this mechanism indicates that the binding of the
molecule to the 30S subunit interferes with 50S subunit
association with the mRNA strand.

45. This results in an unstable ribosomal-mRNA complex, leading to
a frameshift mutation and defective protein synthesis; leading to
cell death.
Humans have ribosomes which are structurally different from
those in bacteria, so the drug does not have this effect in human
cells.
At low concentrations, however, streptomycin only inhibits
growth of the bacteria by inducing prokaryotic ribosomes to
misread mRNA.
Streptomycin is an antibiotic that inhibits both Gram-positive and
Gram-negative bacteria, and is therefore a useful broad-spectrum
antibiotic.

46. 5. CHLOROMYCETIN (CHLORAMPHENICOL)
Chloramphenicol was discovered after being isolated
from Streptomyces venezuelae in 1947.
in 1949 a team of scientists at Parke-Davis including Mildred
Rebstock published their identification of the chemical structure
and their synthesis, making it the first antibiotic to be made
instead of extracted from a microorganism.
It is on the World Health Organization's List of Essential
Medicines. It is available as a generic medication.
Chloramphenicol is an antibiotic useful for the treatment of a
number of bacterial infections.
This includes use as an eye ointment to treat conjunctivitis.

47. By mouth or by injection into a vein, it is used to
treat meningitis, plague, cholera, and typhoid fever.
Common side effects include bone marrow suppression,
nausea, and diarrhea.
The bone marrow suppression may result in death.
Chloramphenicol is a laevorotatory compound.
CHLORAMPHENICOL

48. BIOSYNTHESIS OF CHLORAMPHENICOL

49. Synthesis of chloramphenicol: by Long et. al. (1949).

50. The tetracyclines, a large family of antibiotics, were discovered
by Benjamin Minge Duggar in 1948 as natural products, and first
prescribed in 1948.
Benjamin Duggar, working under Yellapragada
Subbarow at Lederle Laboratories, discovered the first tetracycline
antibiotic, chlortetracycline (Aureomycin), in 1945.
In 1950, Harvard University professor R.B. Woodward, in
collaboration with a group at Pfizer, determined the chemical
structure of the related substance, oxytetracycline (Terramycin).
Tetracycline was patented in 1953 and came into commercial
use in 1978.
6.TETRACYCLINE

51. It is on the World Health Organization's List of Essential
Medicines.
Tetracycline is available as a generic medication. Tetracycline
was originally made from bacteria of the Streptomyces type.
Tetracyclines have a broad spectrum of antibiotic action.
Originally, they possessed some level of bacteriostatic activity
against almost all medically relevant aerobic and
anaerobic bacterial genera, both Gram-positive and Gram-
negative.

53. BIOSYNTHESIS OF OXYTETRACYCLIN

54. Synthesis of a Tetracycline-by R. B. Woodward was reported in 1968

56. TETRACYCLINE

57. Conversion of Aureomycin (Chlortetracycline) to Tetracyclin

58. MECHANISM OF ACTION
Tetracycline inhibits protein synthesis by blocking the
attachment of charged aminoacyl-tRNA to the A site on the
ribosome.
Tetracycline blocks the A-site so that aminoacyl-tRNAs can't
come in. Tetracycline binds to the 30S and 50S subunit of
microbial ribosomes.
Thus, it prevents introduction of new amino acids to the
nascent peptide chain. The action is usually inhibitory and
reversible upon withdrawal of the drug.

59. Mammalian cells are less vulnerable to the effect of
tetracyclines, despite the fact that tetracycline binds to the small
ribosomal subunit of both prokaryotes and eukaryotes (30S and
40S, respectively).
This is because bacteria actively pump tetracycline into
their cytoplasm, even against a concentration gradient, whereas
mammalian cells are simply not affected by the mechanisms of
tetracycline within the cytoplasm.
This accounts for the relatively small off-site effect of
tetracycline on human cells.